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Wednesday, February 22, 2012

Role of PJS gene in breast cancer spread

Last month I got very excited by the following news (two press releases and link to free full text article) about the PJS/LKB1 and breast cancer connection. My excitement multiplied when I realized that the research came from near-to-me UCSF, a place I’ve been treated for metastatic breast cancer for over a decade. I was able to speak with Zena Werb and found that the study has moved to Finland where there are lots of PJS patients. And that they don’t need pathology or cytology donations from anyone local.

Darn! My book club just finished Rebecca Skloot’s Immortal Life of Henrietta Lacks and I was ready to sign up as an informed and willing lab rat. Or at least sign a tissue release form.

Btw, my cancer has progressed dramatically recently and I may need to abandon this semi-neglected blog.

TIA for your healing thoughts and well wishes.

Keep on learning, keep on sharing,

Love,

Stephanie Sugars

Some breast cancer spread may be triggered by a protein, study shows

Discovery points to possible new target for therapy

University of California - San Francisco

16-Jan-2012

Cancers rarely are deadly unless they evolve the ability to grow beyond the tissues in which they first arise. Normally, cells -- even early-stage tumor cells -- are tethered to scaffolding that helps to restrain any destructive tendencies. But scientists from the University of Helsinki, Finland, and from UCSF have identified a cleaver-wielding protein that frees some tumor cells, allowing them to further misbehave.

The protein, they discovered, often blankets the surface of breast tumor cells and can help untether the cells from the matrix of their native tissue. Once released, they may continue to expand their numbers into other tissues where their normal counterparts do not tread.

The protein, called hepsin, is a protease, a class of enzymes that cleaves, or cuts, other proteins. Proteases have been targeted successfully by drugs, and hepsin presents a new possible drug target, the researchers said.

"If we could delay or prevent a tumor from switching from one that grows in place to one that invades, then that would be a major milestone in cancer treatment," said study co-author Zena Werb, PhD, a professor of anatomy at UCSF. Werb has for decades studied the ways in which the behavior of tumor cells is influenced by their surroundings, with a focus on breast tumors.

Working with mouse models of breast development and breast cancer in Werb's UCSF laboratory during a visiting professorship, University of Helsinki scientist Juha Klefström, PhD -- along with Johanna Partanen, a University of Helsinki graduate student -- designed and led experiments that resulted in the discovery of the hepsin protein's role.

Their findings are published in the January 16, 2012 edition of the Proceedings of the American Academy of Sciences (PNAS).

The scientists studied mammary glands in mice and tissue fragments – called organoids – isolated from these glands.

They found that inactivation of a tumor suppressor gene known as liver kinase B1 (Lkb1) caused abnormal development of parts of the mammary gland, including milk-secreting structures. Specifically, they determined that a tightly knit matrix of protein fibers called the basement membrane -- which normally surrounds the milk-secreting structures -- was damaged and degraded.

These events may be triggered in many tumors, the team said, as they found that Lkb1 was abnormally missing in 1 out of every 4 human breast cancer samples they looked at.

Most solid tumors arise from "epithelial" cells, which line the surfaces and cavities of organs. The basement membrane, in turn, lines epithelial cell layers in tissues.

In their mouse studies, the researchers quickly settled on hepsin as a suspect in the destruction of the basement membrane that in turn allows tumor cells to become unbound. In the absence of Lkb1, the protein-cleaving enzyme was abnormally spread over the cell surface. They found that deactivating hepsin allowed the basement membrane to recover.

Graduate student Partanen sought to recapitulate the development of cancer by re-engineering the mice, knocking Lkb1 out of normal mammary epithelial cells. Again, hepsin spread abnormally and basement membrane proteins were sliced and diced. After a year, though, she found that the mice had not grown mammary tumors.

"I was disappointed with the results," she said. "However, then I realized that although broken basement membrane may give cells more freedom to proliferate, the cells may just lay there, resting, and not start to over-proliferate unless they are pushed into cycles of cell division."

Partanen then re-engineered the mice so that they also abnormally activated a gene called Myc, which, is known to help initiate tumors in many tissues, including breast epithelium. She soon saw the mice begin to form tumors.

"We found in our study that genetic removal of hepsin from the mammary gland organoids prevents formation of cancerous tissue," Klefström said. "This finding excites us, as it leads us to think that inhibition of hepsin by drug-like molecules could restrain cancer progression.

"However, we do not know yet if we can cure already-formed tumors by blocking hepsin activity. We need to first improve our experimental systems to properly address this question."

According to Web, "We have observed that loss of Lkb1, combined with activation of a weak inducer of breast cancer – an oncogene such as Myc – can produce aggressive cancers.

"In humans, breast cancers that have diminished amounts of Lkb1 show strong hepsin expression. Since hepsin sits on the cell membrane, it should be accessible to drugs. We believe that hepsin forms a novel target for treatment of a subset of breast cancer patients."

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Scientists from the University of Helsinki and from UCSF have exposed a cell pathway that breast tumor cells use to destruct local tissue neighborhood. Cancer cells may use this pathway to free themselves from mammary epithelial tissue architecture, to spread to surrounding tissues. The cell pathway, the researchers found, is a biochemical chain of events leading to activation of a protein-cleaving enzyme on the surface of the tumor cells.

Cancer rarely kills unless it evolves the ability to spread beyond the tissue in which it developed, to grow into surrounding healthy tissues. An important roadblock for tumor spread is membranous scaffolding, basement membrane, which lines epithelial cell layers in tissues. Normal epithelial cells and even early-stage tumor cells remain tightly tethered to basement membrane, which segregates healthy and likewise cancerous epithelial cells from surrounding tissues. Breakdown of this barrier allows tumor cells to escape from the tethers of the epithelium, launching a tumor invasion to healthy tissues.

Finnish scientists from the University of Helsinki, together with UCSF researchers, have identified a molecular pathway in breast tumor cells leading to activation of a protein-cleaving enzyme hepsin on the surface of breast tumor cells. Tumor cells use hepsin to chop basement membrane proteins - to break free from ties and matrix binding them to local neighborhood in their native epithelial tissue, the investigation suggests. The study will be published in the 16th January edition of the Proceedings of the National Academy of Sciences (PNAS).

"If we could delay or prevent a tumor from switching from one that grows in place to one that invades, then that would be a major milestone in cancer treatment," according to study co-author Zena Werb, PhD, a professor of anatomy at UCSF. Werb has for decades studied the ways in which the behavior of tumor cells is influenced by their surroundings, with a focus on breast tumors.

Working with genetically engineered mouse mammary glands and mammary epithelial fragments isolated from these glands (organoids), University of Helsinki scientist and Finnish Academy Research Fellow Juha Klefström, PhD, along with a University of Helsinki graduate student Johanna Partanen designed and led experiments that resulted in the discovery of a biochemical chain of events that is likely to be initiated by many breast tumor cells when they become invasive.

The research collaborators initially studied a tumor suppressor gene (a gene that prevents the growth of tumors) called Liver Kinase B1 (Lkb1). They found that shutdown of this gene disturbs development of parts of the mammary gland, including milk-secreting tissue structures. Especially, basement membrane, which normally surrounds tissue structures of the mammary gland was damaged and degraded.

A culprit for basement membrane damages was pinpointed: Lkb1 shutdown disconnected hepsin from normal regulation and the protein mistakenly started to blanket the surface of mammary epithelial cells, causing degradation of the basement membrane. Researchers found that inactivation of hepsin allowed the basement membrane to recover. These events may take place in many tumors, as the research found that Lkb1 is missing and hepsin is abnormally expressed in 1 out of 4 human breast cancer samples.

"These findings led us to ask an obvious question: does Hepsin mediated degradation of basement membrane make epithelial cells more cancer-prone?" says Johanna Partanen. She knocked out Lkb1 in the mouse mammary gland. Evidently, hepsin expression was abnormal and basement membrane shattered but even after a year, she did not observe any tumors forming in the glands .

"I was disappointed with the results. However, then I realized that even though broken basement membrane may give more freedom for cells to proliferate, the cells may just lay there, resting, and not start to over-proliferate unless they are pushed to cell division cycle."

Partanen re-engineered mice so that she combined cell cycle "driver" oncogene Myc with inactivated Lkb1 gene in the mammary glands and she soon noticed very fast growing mammary tumors in the mice. "We think that it is the combination of Myc empowered cell cycle and cell's ability to destroy basement membrane, which contributed to the vicious tumor formation" says Partanen.

Will these findings help us to fight cancer? - Maybe, says Juha Klefström: "Hepsin is of a type of protein known as a protease and proteases have been successfully targeted in drug development. We found that deactivation of hepsin in the mammary gland organoids prevents formation of a cancerous phenotype. This finding excites us as it leads us to think that inhibition of Hepsin by drug-like molecules could restrain breast cancer progression. However, we do not know yet if we can cure already formed tumors by blocking hepsin activity. We need to first improve our experimental systems to properly address this question."

According to Zena Werb, "In humans, breast cancers that have diminished amounts of Lkb1 show strong hepsin expression. Since hepsin sits on the cell membrane, it should be accessible to drugs. We believe that hepsin forms a novel target for treatment of a subset of breast cancer patients."

###

Dr Juha Klefström's research group is affiliated with Institute of Biomedicine and Genome-Scale Research Program, Medical Faculty (Biomedicum Helsinki), Unversity of Helsinki. The investigations were carried out as collaboration between four research groups. The collaborating teams were led at the University of Helsinki by Academy of Finland Research Fellow Juha Klefström, Ph.D, Professor Tomi Mäkelä M.D, Ph.D and Docent Panu Kovanen, M.D, Ph.D and at the University of California, San Francisco (UCSF) Professor Zena Werb, Ph.D. Senior coauthors were funded by the Academy of Finland, National Technology Agency TEKES, Sigrid Juselius Foundation, Finish Cancer Organization, K. Albin Johanssons and Paulo Foundations, and US National Cancer Institute and National Institute of Environmental Health Sciences Grants R01 CA057621 and U01 ES019458 (to Z.W.).

XOXOXOX

Tumor suppressor function of Lkb1 is linked to regulation of epithelial integrity

aInstitute of Biomedicine and Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland; bInstitute of Biotechnology, University of Helsinki, 00014, Helsinki, Finland; cDepartment of Anatomy, University of California, San Francisco, CA 94143; and dDepartment of Immunology and Pathology, Haartman Institute, University of Helsinki, 00014, Helsinki, Finland

Contributed by Zena Werb, December 14, 2011 (sent for review November 11, 2011)